This laboratory has been investigating the genetic and biochemical changes associated with drug resistance in human breast cancer cells as well as studies on the cell cycle regulation of human mammary epithelial cells. We have identified a number of changes associated with the development of multi-drug resistance including overexpression of the mdr1/P-glycoprotein drug efflux pump as well as changes in the number of drug metabolizing enzymes including glutathione transferase and the selenium dependent glutathione peroxidase gene. We have initiated studies on the role of these genes in development of resistance as well as on the regulation of expression of these genes in sensitive and drug resistant breast cancer cells. We have analyzed the transcription and posttranscriptional control mechanisms involved in the regulation of expression of the human mdr1 gene, the human pi class glutathione transferase gene, and the human selenium dependent glutathione peroxidase one gene. We have also isolated non-P-glycoprotein expressing multidrug resistant cell lines. In one of these, we have found amplification and overexpression of the MRP (multidrug resistance associated protein) gene. The role of this gene in drug resistance is currently being studied.